Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease

Park,Soo-Yeon; Kim,Mi-Jeong; Kim,Young  Jun; Lee,Yoo-Hyun; Bae,Donghyuk; Kim,Sunoh; Na,Younghwa; Yoon,Ho-Geun

doi:10.3892/ijmm.2015.2099

Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease

Authors:
- Soo-Yeon Park
- Mi-Jeong Kim
- Young Jun Kim
- Yoo-Hyun Lee
- Donghyuk Bae
- Sunoh Kim
- Younghwa Na
- Ho-Geun Yoon
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Affiliations: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea, Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea, Department of Food and Nutrition, The University of Suwon, Kyunggi-do, Republic of Korea, Jeollanamdo Institute of Natural Resources Research, Jeonnam, Republic of Korea, College of Pharmacy, CHA University, Pocheon, Republic of Korea
Published online on: February 12, 2015 https://doi.org/10.3892/ijmm.2015.2099
Pages: 1109-1118

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Abstract

Several recent studies have reported an association between neurodegeneration and histone modifications, such as acetylation, deacetylation and methylation. In addition, questions have been raised regarding a potential functional role for the histone acetylation enzymes in β-amyloid (Aβ)-mediated neurotoxicity, particularly the p300/CBP-associated factor (PCAF) enzyme. We recently reported the potential utility of a PCAF inhibitor in the suppression of Aβ-induced neuronal cell death, although the in vivo effectiveness of the PCAF inhibitor remained unclear. In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats. In conclusion, our results demonstrate that this selective PCAF inhibitor has the potential to reduce the neuroinflammatory response induced by Aβ.

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